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1.
Nutrients ; 13(2)2021 Jan 23.
Article in English | MEDLINE | ID: covidwho-1575478

ABSTRACT

SARS-CoV-2 is a newly emerging virus that currently lacks curative treatments. Lactoferrin (LF) is a naturally occurring non-toxic glycoprotein with broad-spectrum antiviral, immunomodulatory and anti-inflammatory effects. In this study, we assessed the potential of LF in the prevention of SARS-CoV-2 infection in vitro. Antiviral immune response gene expression was analyzed by qRT-PCR in uninfected Caco-2 intestinal epithelial cells treated with LF. An infection assay for SARS-CoV-2 was performed in Caco-2 cells treated or not with LF. SARS-CoV-2 titer was determined by qRT-PCR, plaque assay and immunostaining. Inflammatory and anti-inflammatory cytokine production was determined by qRT-PCR. LF significantly induced the expression of IFNA1, IFNB1, TLR3, TLR7, IRF3, IRF7 and MAVS genes. Furthermore, LF partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells. Our in vitro data support LF as an immune modulator of the antiviral immune response with moderate effects against SARS-CoV-2 infection.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 , Gene Expression Regulation , Immunity, Innate/drug effects , Lactoferrin/pharmacology , SARS-CoV-2/immunology , Animals , COVID-19/immunology , COVID-19/pathology , COVID-19/prevention & control , Caco-2 Cells , Chlorocebus aethiops , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Humans , Vero Cells
2.
Biol Pharm Bull ; 44(11): 1617-1634, 2021.
Article in English | MEDLINE | ID: covidwho-1551286

ABSTRACT

The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Animals , COVID-19/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Humans , Liver Diseases/metabolism , Protein Isoforms/metabolism
3.
Cell Transplant ; 30: 9636897211054481, 2021.
Article in English | MEDLINE | ID: covidwho-1511642

ABSTRACT

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/complications , Interleukin-6/biosynthesis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/metabolism , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neutralizing/immunology , Cells, Cultured , Coculture Techniques , Combined Modality Therapy , DNA, Complementary/genetics , Gene Expression Regulation/drug effects , Humans , Inflammation , Interleukin-6/genetics , Interleukin-6/pharmacology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation/drug effects , Phytohemagglutinins/pharmacology , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/biosynthesis , Receptors, Interleukin-6/genetics , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Umbilical Cord/cytology
4.
J Ethnopharmacol ; 283: 114701, 2022 Jan 30.
Article in English | MEDLINE | ID: covidwho-1446835

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanfei Baidu Decoction (XFBD), one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, plays an important role in the treatment of mild and/or common patients with dampness-toxin obstructing lung syndrome. AIM OF THE STUDY: The present work aims to elucidate the protective effects and the possible mechanism of XFBD against the acute inflammation and pulmonary fibrosis. METHODS: We use TGF-ß1 induced fibroblast activation model and LPS/IL-4 induced macrophage inflammation model as in vitro cell models. The mice model of lung fibrosis was induced by BLM via endotracheal drip, and then XFBD (4.6 g/kg, 9.2 g/kg) were administered orally respectively. The efficacy and molecular mechanisms in the presence or absence of XFBD were investigated. RESULTS: The results proved that XFBD can effectively inhibit fibroblast collagen deposition, down-regulate the level of α-SMA and inhibit the migration of fibroblasts. IL-4 induced macrophage polarization was also inhibited and the secretions of the inflammatory factors including IL6, iNOS were down-regulated. In vivo experiments, the results proved that XFBD improved the weight loss and survival rate of the mice. The XFBD high-dose administration group had a significant effect in inhibiting collagen deposition and the expression of α-SMA in the lungs of mice. XFBD can reduce bleomycin-induced pulmonary fibrosis by inhibiting IL-6/STAT3 activation and related macrophage infiltration. CONCLUSIONS: Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.


Subject(s)
COVID-19/drug therapy , Drugs, Chinese Herbal , Inflammation/drug therapy , Macrophages/drug effects , SARS-CoV-2 , Signal Transduction/drug effects , Animals , Cell Survival/drug effects , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Fibroblasts/drug effects , Gene Expression Regulation/drug effects , Gene Regulatory Networks , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Phytotherapy , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/prevention & control , RAW 264.7 Cells , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism
5.
Cells ; 10(9)2021 09 04.
Article in English | MEDLINE | ID: covidwho-1403545

ABSTRACT

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood-brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-ß and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-ß agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-ß antagonists, respectively, confirming the role of ER-α and ER-ß in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.


Subject(s)
Brain/blood supply , Cell Movement/drug effects , Estradiol/pharmacology , Gene Expression Profiling , Pericytes/cytology , Cell Movement/genetics , Cell Proliferation/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Regulation/drug effects , Humans , Mitogen-Activated Protein Kinases/metabolism , Pericytes/drug effects , Pericytes/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Estrogen/metabolism , Tumor Necrosis Factor-alpha/metabolism
6.
Mol Med ; 27(1): 105, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1403209

ABSTRACT

BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. RESULTS: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2's main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. CONCLUSIONS: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.


Subject(s)
Antiviral Agents/pharmacology , Atorvastatin/pharmacology , COVID-19/drug therapy , Lung/drug effects , Organoids/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Atorvastatin/chemistry , COVID-19/prevention & control , Cell Line , Coronavirus 3C Proteases/chemistry , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Doxycycline/pharmacology , Drug Approval , Drug Repositioning , Gene Expression Regulation/drug effects , Humans , Lung/virology , Models, Biological , Molecular Docking Simulation , Organoids/virology , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Trifluoperazine/chemistry , Trifluoperazine/pharmacology , United States , United States Food and Drug Administration , Vesiculovirus/genetics , Virus Internalization/drug effects
7.
Biomed Pharmacother ; 143: 112095, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1392164

ABSTRACT

Angiotensin-converting enzyme-2 (ACE2) is one of the major components of the renin-angiotensin system (RAS) and participates in the physiological functions of the cardiovascular system and lungs. Recent studies identified ACE2 as the receptor for the S-protein of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and thus acts as the gateway for viral entry into the human body. Virus infection causes an imbalance in the RAS axis and induces acute lungs injury and fibrosis. Various factors regulate ACE2 expression patterns as well as control its epigenetic status at both transcription and translational levels. This review is mainly focused on the impact of environmental toxicants, drugs, endocrine disruptors, and hypoxia as controlling parameters for ACE2 expression and its possible modulation by epigenetic changes which are marked by DNA methylation, histone modifications, and micro-RNAs (miRNAs) profile. Furthermore, we have emphasized on interventions of various phytochemicals and bioactive compounds as epidrugs that regulate ACE2-S-protein interaction and thereby curb viral infection. Since ACE2 is an important component of the RAAS axis and a crucial entry point of SARS-CoV-2, the dynamics of ACE2 expression in response to various extrinsic and intrinsic factors are of contemporary relevance. We have collated updated information on ACE2 expression modulated by epidrugs, and urge to take over further studies on these important physiological regulators to unravel many more systemic linkages related to both metabolic and infectious diseases, in general and SARS-CoV-2 in particular for further development of targeted interventions.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19 , Epigenesis, Genetic , Hazardous Substances , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Hazardous Substances/adverse effects , Hazardous Substances/metabolism , Humans , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Virus Internalization
9.
Signal Transduct Target Ther ; 5(1): 218, 2020 10 03.
Article in English | MEDLINE | ID: covidwho-1387198

Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cardiac Glycosides/pharmacology , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/drug effects , Animals , Antiviral Agents/chemistry , Betacoronavirus/pathogenicity , Biological Products/chemistry , Biological Products/pharmacology , Bufanolides/chemistry , Bufanolides/pharmacology , COVID-19 , Cardiac Glycosides/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Digoxin/chemistry , Digoxin/pharmacology , High-Throughput Screening Assays , Host-Pathogen Interactions/genetics , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Janus Kinases/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Pandemics , Phenanthrenes/chemistry , Phenanthrenes/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Vero Cells , Virus Replication/drug effects
10.
Zool Res ; 42(5): 633-636, 2021 Sep 18.
Article in English | MEDLINE | ID: covidwho-1369995

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Numerous studies have demonstrated that cardiovascular disease may affect COVID-19 progression. In the present study, we investigated the effect of hypertension on viral replication and COVID-19 progression using a hypertensive mouse model infected with SARS-CoV-2. Results revealed that SARS-CoV-2 replication was delayed in hypertensive mouse lungs. In contrast, SARS-CoV-2 replication in hypertensive mice treated with the antihypertensive drug captopril demonstrated similar virus replication as SARS-CoV-2-infected normotensive mice. Furthermore, antihypertensive treatment alleviated lung inflammation induced by SARS-CoV-2 replication (interleukin (IL)-1ß up-regulation and increased immune cell infiltration). No differences in lung inflammation were observed between the SARS-CoV-2-infected normotensive mice and hypertensive mice. Our findings suggest that captopril treatment may alleviate COVID-19 progression but not affect viral replication.


Subject(s)
Antihypertensive Agents/therapeutic use , COVID-19/complications , Captopril/therapeutic use , Hypertension/complications , Lung Diseases/drug therapy , SARS-CoV-2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Gene Expression Regulation/drug effects , Inflammation/complications , Inflammation/drug therapy , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lung Diseases/etiology , Lung Diseases/virology , Mice , Virus Replication/drug effects
11.
Sci Rep ; 11(1): 16629, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361646

ABSTRACT

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/agonists , COVID-19/drug therapy , Carbazoles/pharmacology , Omeprazole/pharmacology , Receptors, Aryl Hydrocarbon/agonists , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/virology , Carbazoles/therapeutic use , Chlorocebus aethiops , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Hep G2 Cells , Humans , Omeprazole/therapeutic use , RNA-Seq , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Vero Cells , Virus Internalization/drug effects
12.
Molecules ; 26(15)2021 Jul 22.
Article in English | MEDLINE | ID: covidwho-1346513

ABSTRACT

Prunus mahaleb L. fruit has long been used in the production of traditional liqueurs. The fruit also displayed scavenging and reducing activity, in vitro. The present study focused on unravelling peripheral and central protective effects, antimicrobial but also anti-COVID-19 properties exerted by the water extract of P. mahaleb. Anti-inflammatory effects were studied in isolated mouse colons exposed to lipopolysaccharide. Neuroprotection, measured as a blunting effect on hydrogen-peroxide-induced dopamine turnover, was investigated in hypothalamic HypoE22 cells. Antimicrobial effects were tested against different Gram+ and Gram- bacterial strains. Whereas anti-COVID-19 activity was studied in lung adenocarcinoma H1299 cells, where the gene expression of ACE2 and TMPRSS2 was measured after extract treatment. The bacteriostatic effects induced on Gram+ and Gram- strains, together with the inhibition of COX-2, TNFα, HIF1α, and VEGFA in the colon, suggest the potential of P. mahaleb water extract in contrasting the clinical symptoms related to ulcerative colitis. The inhibition of the hydrogen peroxide-induced DOPAC/DA ratio indicates promising neuroprotective effects. Finally, the downregulation of the gene expression of ACE2 and TMPRSS2 in H1299 cells, suggests the potential to inhibit SARS-CoV-2 virus entry in the human host. Overall, the results support the valorization of the local cultivation of P. mahaleb.


Subject(s)
Bacteria/drug effects , Colon/drug effects , Neuroprotection , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19 , Cell Line , Colitis, Ulcerative/drug therapy , Cytokines/genetics , Cytokines/metabolism , Dopamine/metabolism , Fruit/chemistry , Gene Expression Regulation/drug effects , HCT116 Cells , Humans , Inflammation/drug therapy , Male , Mice , Plant Extracts/chemistry , Prunus/chemistry , Serine Endopeptidases/metabolism
13.
Genes Dev ; 35(13-14): 1005-1019, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1334329

ABSTRACT

N6-methyladenosine (m6A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected and virus-infected cells. Installation of m6A by the nuclear RNA methyltransferase METTL3 occurs cotranscriptionally; however, the genomes of some cytoplasmic RNA viruses are also m6A-modified. How the cellular m6A modification machinery impacts coronavirus replication, which occurs exclusively in the cytoplasm, is unknown. Here we show that replication of SARS-CoV-2, the agent responsible for the COVID-19 pandemic, and a seasonal human ß-coronavirus HCoV-OC43, can be suppressed by depletion of METTL3 or cytoplasmic m6A reader proteins YTHDF1 and YTHDF3 and by a highly specific small molecule METTL3 inhibitor. Reduction of infectious titer correlates with decreased synthesis of viral RNAs and the essential nucleocapsid (N) protein. Sites of m6A modification on genomic and subgenomic RNAs of both viruses were mapped by methylated RNA immunoprecipitation sequencing (meRIP-seq). Levels of host factors involved in m6A installation, removal, and recognition were unchanged by HCoV-OC43 infection; however, nuclear localization of METTL3 and cytoplasmic m6A readers YTHDF1 and YTHDF2 increased. This establishes that coronavirus RNAs are m6A-modified and host m6A pathway components control ß-coronavirus replication. Moreover, it illustrates the therapeutic potential of targeting the m6A pathway to restrict coronavirus reproduction.


Subject(s)
Coronavirus OC43, Human/physiology , RNA Processing, Post-Transcriptional/genetics , SARS-CoV-2/physiology , Virus Replication/genetics , Adenosine/analogs & derivatives , Adenosine/genetics , Adenosine/metabolism , Cell Line , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/drug effects , Humans , Methyltransferases/antagonists & inhibitors , Methyltransferases/metabolism , Nucleocapsid Proteins , RNA, Viral/metabolism , RNA-Binding Proteins/metabolism , Virus Replication/drug effects
14.
J Nutr Biochem ; 98: 108821, 2021 12.
Article in English | MEDLINE | ID: covidwho-1309296

ABSTRACT

Membrane glycoprotein is the most abundant protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but its role in coronavirus disease 2019 (COVID-19) has not been fully characterized. Mice intranasally inoculated with membrane glycoprotein substantially increased the interleukin (IL)-6, a hallmark of the cytokine storm, in bronchoalveolar lavage fluid (BALF), compared to mice inoculated with green fluorescent protein (GFP). The high level of IL-6 induced by membrane glycoprotein was significantly diminished in phosphodiesterase 4 (PDE4B) knockout mice, demonstrating the essential role of PDE4B in IL-6 signaling. Mycelium fermentation of Lactobacillus rhamnosus (L. rhamnosus) EH8 strain yielded butyric acid, which can down-regulate the PDE4B expression and IL-6 secretion in macrophages. Feeding mice with mycelia increased the relative abundance of commensal L. rhamnosus. Two-week supplementation of mice with L. rhamnosus plus mycelia considerably decreased membrane glycoprotein-induced PDE4B expression and IL-6 secretion. The probiotic activity of L. rhamnosus plus mycelia against membrane glycoprotein was abolished in mice treated with GLPG-0974, an antagonist of free fatty acid receptor 2 (Ffar2). Activation of Ffar2 in the gut-lung axis for down-regulation of the PDE4B-IL-6 signalling may provide targets for development of modalities including probiotics for treatment of the cytokine storm in COVID-19.


Subject(s)
Coronavirus M Proteins/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Interleukin-6/metabolism , Lactobacillus rhamnosus/physiology , Probiotics/pharmacology , SARS-CoV-2/metabolism , Animals , Butyric Acid , Cell Line , Cloning, Molecular , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Female , Fermentation , Gene Expression Regulation/drug effects , Humans , Interleukin-6/genetics , Mice , Mice, Inbred ICR , Receptors, G-Protein-Coupled/metabolism
15.
Genes (Basel) ; 11(6)2020 06 26.
Article in English | MEDLINE | ID: covidwho-1280752

ABSTRACT

Ivermectin (IVM), an antiparasitic drug, has a positive effect against Anisakis simplex s.s. infection and has been used for the treatment and prevention of anisakiasis in humans. However, the molecular mechanism of action of IVM on A. simplex s.s. remains unknown. Herein, tandem mass tag (TMT) labeling and extensive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis were used to identify the effect of IVM on the proteome of A. simplex s.s. in vitro. During the study, 3433 proteins, of which 1247 had at least two protein unique peptides, were identified. Comparative proteomics analysis revealed that 59 proteins were differentially regulated (DRPs) in IVM-treated larvae, of which 14 proteins were upregulated and 38 were downregulated after 12 h of culture, but after 24 h, 12 proteins were upregulated and 22 were downregulated. The transcription level of five randomly selected DRPs was determined by real-time PCR as a supplement to the proteomic data. The functional enrichment analysis showed that most of the DRPs were involved in oxidoreductase activity, immunogenicity, protein degradation, and other biological processes. This study has, for the first time, provided comprehensive proteomics data on A. simplex s.s. response to IVM and might deliver new insight into the molecular mechanism by which IVM acts on invasive larvae of A. simplex s.s.


Subject(s)
Anisakiasis/genetics , Anisakis/drug effects , Ivermectin/pharmacology , Proteome/genetics , Animals , Anisakiasis/drug therapy , Anisakiasis/parasitology , Anisakis/pathogenicity , Chromatography, Liquid , Gene Expression Regulation/drug effects , Humans , Larva/drug effects , Larva/pathogenicity , Proteomics , Tandem Mass Spectrometry
16.
Int J Biol Macromol ; 184: 297-312, 2021 Aug 01.
Article in English | MEDLINE | ID: covidwho-1265684

ABSTRACT

COVID-19 caused by SARS-CoV-2 corona virus has become a global pandemic. In the absence of drugs and vaccine, and premises of time, efforts and cost required for their development, natural resources such as herbs are anticipated to provide some help and may also offer a promising resource for drug development. Here, we have investigated the therapeutic prospective of Ashwagandha for the COVID-19 pandemic. Nine withanolides were tested in silico for their potential to target and inhibit (i) cell surface receptor protein (TMPRSS2) that is required for entry of virus to host cells and (ii) viral protein (the main protease Mpro) that is essential for virus replication. We report that the withanolides possess capacity to inhibit the activity of TMPRSS2 and Mpro. Furthermore, withanolide-treated cells showed downregulation of TMPRSS2 expression and inhibition of SARS-CoV-2 replication in vitro, suggesting that Ashwagandha may provide a useful resource for COVID-19 treatment.


Subject(s)
Antiviral Agents/pharmacology , Plant Extracts/chemistry , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Viral Matrix Proteins/metabolism , Withanolides/pharmacology , A549 Cells , Antiviral Agents/chemistry , Cell Line , Cell Survival/drug effects , Computer Simulation , Down-Regulation , Gene Expression Regulation/drug effects , Humans , MCF-7 Cells , Models, Molecular , Molecular Dynamics Simulation , Protein Conformation , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Viral Matrix Proteins/chemistry , Virus Internalization/drug effects , Withanolides/chemistry
17.
Open Biol ; 11(6): 210069, 2021 06.
Article in English | MEDLINE | ID: covidwho-1261130

ABSTRACT

The COVID-19 pandemic has wreaked unprecedented societal havoc worldwide. The infected individuals may present mild to severe symptoms, with nearly 20% of the confirmed patients impaired with significant complications, including multi-organ failure. Acute respiratory distress imposed by SARS-CoV-2 largely results from an aggravated cytokine storm and deregulated immune response. The forkhead box O (FoxO) transcription factors are reported to play a significant role in maintaining normal cell physiology by regulating survival, apoptosis, oxidative stress, development and maturation of T and B lymphocytes, secretion of inflammatory cytokines, etc. We propose a potent anti-inflammatory approach based on activation of the FoxO as an attractive strategy against the novel coronavirus. This regime will be focused on restoring redox and inflammatory homeostasis along with repair of the damaged tissue, activation of lymphocyte effector and memory cells. Repurposing FoxO activators as a means to alleviate the inflammatory burst following SARS-CoV-2 infection can prove immensely valuable in the ongoing pandemic and provide a reliable groundwork for enriching our repertoire of antiviral modalities for any such complication in the future. Altogether, our review highlights the possible efficacy of FoxO activation as a novel arsenal for clinical management of COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Forkhead Transcription Factors/metabolism , Host-Pathogen Interactions , SARS-CoV-2/physiology , Biomarkers , COVID-19/drug therapy , COVID-19/epidemiology , Cytokines/metabolism , Disease Management , Disease Susceptibility , Drug Discovery , Gene Expression Regulation/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Inflammation/drug therapy , Inflammation/etiology , Inflammation/metabolism , Inflammation Mediators/metabolism , Molecular Targeted Therapy , Oxidation-Reduction , Signal Transduction
18.
Stem Cells Dev ; 30(15): 758-772, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1254367

ABSTRACT

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.


Subject(s)
Cytokine Release Syndrome/prevention & control , Extracellular Vesicles/physiology , Mesenchymal Stem Cells/cytology , SARS-CoV-2/physiology , Wharton Jelly/cytology , Adult , Aged , COVID-19/blood , COVID-19/complications , COVID-19/metabolism , COVID-19/therapy , Cells, Cultured , Coculture Techniques , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/genetics , Cytokines/metabolism , Diabetes Complications/blood , Diabetes Complications/metabolism , Diabetes Complications/therapy , Diabetes Complications/virology , Diabetes Mellitus/blood , Diabetes Mellitus/metabolism , Diabetes Mellitus/therapy , Diabetes Mellitus/virology , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Glucose/metabolism , Glucose/pharmacology , Humans , Inflammation Mediators/metabolism , Male , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/physiology , Pregnancy , Toxins, Biological/metabolism , Toxins, Biological/pharmacology , Umbilical Cord/cytology , Uremia/blood , Uremia/complications , Uremia/metabolism , Uremia/therapy
19.
Sci Rep ; 11(1): 11130, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1246392

ABSTRACT

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Lung/drug effects , Receptors, Androgen/metabolism , Serine Endopeptidases/metabolism , Androgen Receptor Antagonists/pharmacology , Androgens , Angiotensin-Converting Enzyme 2/genetics , Animals , Benzamides/pharmacology , COVID-19/genetics , Cell Line, Tumor , Chromatin Immunoprecipitation Sequencing , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Humans , Immunohistochemistry , Lung/metabolism , Lung/virology , Male , Mice , Nitriles/pharmacology , Phenylthiohydantoin/pharmacology , Serine Endopeptidases/genetics , Smokers
20.
Sci Rep ; 11(1): 10763, 2021 05 24.
Article in English | MEDLINE | ID: covidwho-1242041

ABSTRACT

Research on drugs against SARS-CoV-2 (cause of COVID-19) has been one of the major world concerns at present. There have been abundant research data and findings in this field. The interference of drugs on gene expression in cell lines, drug-target, protein-virus receptor networks, and immune cell infiltration of the host may provide useful information for anti-SARS-CoV-2 drug research. To simplify the complex bioinformatics analysis and facilitate the evaluation of the latest research data, we developed OmiczViz ( http://medcode.link/omicsviz ), a web tool that has integrated drug-cell line interference data, virus-host protein-protein interactions, and drug-target interactions. To demonstrate the usages of OmiczViz, we analyzed the gene expression data from cell lines treated with chloroquine and ruxolitinib, the drug-target protein networks of 48 anti-coronavirus drugs and drugs bound with ACE2, and the profiles of immune cell infiltration between different COVID-19 patient groups. Our research shows that chloroquine had a regulatory role of the immune response in renal cell line but not in lung cell line. The anti-coronavirus drug-target network analysis suggested that antihistamine of promethaziney and dietary supplement of Zinc might be beneficial when used jointly with antiviral drugs. The immune infiltration analysis indicated that both the COVID-19 patients admitted to the ICU and the elderly with infection showed immune exhaustion status, yet with different molecular mechanisms. The interactive graphic interface of OmiczViz also makes it easier to analyze newly discovered and user-uploaded data, leading to an in-depth understanding of existing findings and an expansion of existing knowledge of SARS-CoV-2. Collectively, OmicsViz is web program that promotes the research on medical agents against SARS-CoV-2 and supports the evaluation of the latest research findings.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , User-Computer Interface , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Cell Line , Chloroquine/pharmacology , Gene Expression Regulation/drug effects , Humans , Internet , Nitriles , Protein Binding , Pyrazoles/pharmacology , Pyrimidines , Severity of Illness Index
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